Field of the Invention
The present invention relates to an anti-cancer composition containing Wnt decoy receptor which inhibits activation of Wnt signaling involved in tumor development.
Description of the Related Art
Lung cancer is highly aggressive and the most common cause of cancer-related deaths worldwide. In 2009, the American Cancer Society estimated that there were 219,440 new cases of lung cancer in the United States. Standard therapies such as surgery and radiation are not effective in many cases (1); however, an increased understanding of the molecular mechanisms of lung cancer has led to the development of promising new therapies (2). Although chemotherapy advances have improved overall survival for patients with aggressive non-small cell lung cancer, chemoresistance remains a major cause of treatment failure (3). Activating mutations in the epithelial growth factor receptor (EGFR) are present in a subset of lung adenocarcinomas, making these tumors highly resistant to EGFR tyrosine kinase inhibitors gefitinib and erlotinib (4, 5). Many aggressive lung cancers show alterations in various cancer-associated genes, including Wnt, K-ras, extracellular signal-regulated kinase (ERK), Akt, and cyclooxygenase-2, suggesting a different molecular pathway for carcinogenesis in lung adenocarcinomas (6-8).
The role of Wnt signaling in cancer was first suggested 20 years ago with the discovery of Wnt-1 as an integration site for mouse mammary tumor virus (9). Many studies have reported that altered expression of Wnt ligands, receptors, and extracellular antagonists are associated with cancer development/progression and stem cell self-renewal/differentiation (10). Expression of the Wnt ligand, low-density lipoprotein receptor-related protein 5 (LRP5), and LRP6 are upregulated in lung cancers, whereas Wnt antagonists that bind Wnt ligands to block interaction with receptors (e.g., Wnt inhibitory factor-1 (WIF-1), secreted Frizzled-related proteins (sFRP) and dickkopf proteins (DKK) are downregulated or inactivated (11, 12). Accordingly, monoclonal antibodies and small interfering RNAs against Wnt and overexpression of Wnt antagonists suppress tumor growth in various in vitro and in vivo tumor models.
LRP6, a member of the LRP superfamily, is required for activation of the canonical Wnt signaling pathway, which leads to the stabilization and nuclear translocation of β-catenin, the key effector molecule (13). LRP6 consists of four distinct YWTD β-propeller/EGF-like domain pairs; the first and second YWTD domains (E1 and E2) are required for binding to Wnt (14-16). In the present study, we explored the therapeutic utility of a novel soluble Wnt receptor, sLRP6E1E2, which is composed of the LRP6 E1 and E2 regions. We examined the biological effects of sLRP6E1E2 binding to extracellular Wnt ligands and blocking ligand-receptor interactions. The results of the present invention provide direct evidence that specific Wnt ligand/receptor interactions have potential use as anticancer therapeutic agents.
Throughout this application, various publications and patents are referred and citations are provided in parentheses. The disclosures of these publications and patents in their entities are hereby incorporated by references into this application in order to fully describe this invention and the state of the art to which this invention pertains.